59 Thus, a

clear gender difference was observed. Our subsequent studies of dynorphin effects now must be done always considering males and females separately. In a second set of studies, we have addressed the question of whether or not the dynorphin responsivity, with respect to lowering dopaminergic tone, will occur similarly in healthy long-term well-stabilized methadonemaintained subjects.61 Two doses of dynorphin Inhibitors,research,lifescience,medical again were used for study in both a new group of healthy volunteer subjects and in a group of long-term stable methadonemaintained patients.61 Again, in the healthy volunteer subjects, a dose-dependent rise in serum prolactin was observed after dynorphin administration.61 Similarly, in the methadone-maintained patients (receiving 80 to 120 mg/day of methadone), Inhibitors,research,lifescience,medical a dose-dependent rise in prolactin occurs.61 Because years ago (published in 1978 by our group), we had shown that methadone itself, acting as a mu opioid receptor agonist, acts to lower dopaminergic tone, causes increase in serum prolactin, which occurs at time of peak plasma levels of methadone (that is, around 2 to 4 hours after oral methadone

dose), in the dynorphin studies, Inhibitors,research,lifescience,medical we withheld the methadone dose until 60 minutes after the dynorphin was given.62 In these subjects, as in our much earlier studies, we showed a second and separate brisk rise in prolactin levels, beginning at 2 hours after methadone administration and remaining elevated at Inhibitors,research,lifescience,medical 5 hours after methadone administration. Again, in the methadone-maintained patients, as in both groups of healthy volunteer subjects, there was a dose-dependent dynorphin-induced rise in prolactin levels which returned to basal levels by 90 to 120 minutes. Thus, in this study, we were able to observe both the dynorphin- and methadone-induced lowering of tuberoinfundibular Inhibitors,research,lifescience,medical dopaminergic tone, resulting in both rises in serum prolactin levels.61,62 In yet another series of studies, we had observed that when given to healthy volunteers nalmefene caused a small but modest

rise in serum prolactin levels.53 Therefore, we entered into a all collaboration with Bidlack, and in that collaboration addressed directly the issue of whether the kappa opioid receptor selleckchem activity of nalmefene is antagonist, or possibly, as we hypothesized, partial agonist. It was found clearly that nalmefene possesses kappa-opioid receptor partial agonist activity in in vitro studies using appropriate molecular cellular constructs.53 It was reconfirmed that the mu opioid receptor action of nalmefene is only that of antagonism; the kappa opioid receptor action is both agonism (partial agonist) and antagonism.53 Further, we were able to show that nalmefene effects a modest elevation of prolactin levels, suggesting a modest lowering of dopaminergic tone.